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High-throughput single-cell heterogeneity imaging and analysis is essential for understanding complex biological systems and for advancing personalized precision disease diagnosis and treatment. Here, we present a miniaturized lensless chemiluminescence chip for high-throughput single-cell functional imaging with subcellular resolution. With the sensitive chemiluminescence sensing and wide field of view of contact lensless imaging, we demonstrated the chemiluminescent imaging of over 1000 single cells, and their membrane glycoprotein and the high-throughput single-cell heterogeneity of membrane protein imaging were examined for precision analysis. Furthermore, the functional adhesion and heterogeneity of single live cells were imaged and explored. This miniaturized lensless on-chip CL-CMOS imaging platform enables high-throughput single-cell imaging and analysis with high sensitivity and subcellular resolution, providing new techniques for the cellular study of biological heterogeneity and has potential application in precision disease diagnosis and treatment at the point-of-care settings.

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Background: Several studies have shown that the survival outcomes of chemoradiotherapy (CRT) are not inferior to surgery alone in patients with esophageal squamous cell carcinoma (ESCC). This study aimed to compare survival outcomes of ESCC treated with immunochemotherapy (ICT) followed by surgery or definitive CRT and to explore subgroups of patients who could benefit from one treatment strategy., Methods: Pooled data were obtained from two prospectively registered clinical trials of patients with ESCC at the Affiliated Cancer Hospital of Nanjing Medical University. One trial involved treatment with neoadjuvant ICT followed by surgery, while the other involved induction ICT followed by definitive CRT. To balance potential biases, we conducted an overlap weighting (OW) analysis to compare the rates of 2-year progression-free survival (PFS), locoregional relapse-free survival (LRRFS), distant relapse-free survival (DRFS), and overall survival (OS). Additionally, propensity score matching (PSM) was performed to analyze failure pattern., Results: The median follow-up time of the survivors was 39.3 months. After overlap weighting, the rates of 2-year PFS, LRRFS, DRFS, and OS for patients undergoing surgery and CRT were 61.5 % and 59.7 %, 67.2 % and 69.9 %, 81.3 % and 90.7 %, 84.6 % and 79.1 %, respectively (P>.05 for all). A trend for improved 2-year OS was observed in the surgery group in patients who did not respond to ICT (P=.07)., Conclusion: The differences in the rates of 2-year PFS, LRRFS, DRFS, and OS between the surgery group and the chemoradiotherapy group did not reach statistical significance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The plastid-encoded RNA polymerase serves as the principal transcription machinery within chloroplasts, transcribing over 80% of all primary plastid transcripts. This polymerase consists of a prokaryotic-like core enzyme known as the plastid-encoded RNA polymerase core, and is supplemented by newly evolved associated proteins known as PAPs. However, the architecture of the plastid-encoded RNA polymerase and the possible functions of PAPs remain unknown. Here, we present the cryo-electron microscopy structure of a 19-subunit plastid-encoded RNA polymerase complex derived from spinach (Spinacia oleracea). The structure shows that the plastid-encoded RNA polymerase core resembles bacterial RNA polymerase. Twelve PAPs and two additional proteins (FLN2 and pTAC18) bind at the periphery of the plastid-encoded RNA polymerase core, forming extensive interactions that may facilitate complex assembly and stability. PAPs may also protect the complex against oxidative damage and has potential functions in transcriptional regulation. This research offers a structural basis for future investigations into the functions and regulatory mechanisms governing the transcription of plastid genes., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The production of short-chain fatty acids (SCFAs) from sludge is promising, but the efficiency and product quality often vary because of extracellular polymeric substances (EPS) characteristics and pretreatment principles. This study adopted specific EPS disintegration pretreatment to treat different types of sludge. By correlation coefficient matrix analysis and correlation dynamics change resolution, the intrinsic relationships between the nature of EPS and the production of SCFAs from sludge was unveiled. We demonstrate that tight-bound EPS (TB-EPS) is a principal carbon reservoir, positively impacting SCFAs yields, in the fermentation system with EPS as the main fermentation substrate, it can contribute about 29.2 % for SCFAs growth during fermentation. Conversely, TB-EPS exhibits a negative correlation during fermentation due to EPS-SCFAs interconversion, while loosely bound EPS (LB-EPS) correlates positively. Proteins and polysaccharides in TB-EPS, especially proteins, significantly enhance individual SCFAs yields, predominantly acetic, propionic, and isovaleric acids. The findings would provide a theoretical basis for developing pretreatments and process-control technologies aimed at improving SCFAs production efficiency and quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Cataract remains the primary cause of blindness in middle-income and low-income countries, with a known association with environmental factors including smoking. However, the relationship between early-life tobacco smoke exposures, including in utero tobacco smoke exposure and early initiation of smoking, and the risk of cataract incidence remains unclear. We aimed to examine the associations of early-life exposure to tobacco smoke with the risk of elderly-onset cataract., Methods: In this prospective study, we included 330,528 participants aged 40 years or older who were recruited between 2006 and 2010. Early-life tobacco smoke exposures, including in utero, childhood, and adolescence exposure to tobacco smoke, as well as the type of tobacco smoke, were ascertained based on questionnaires at baseline. Elderly-onset cataract was ascertained using hospital inpatient records and cataract surgery records. Multivariable-adjusted Cox proportional hazards models were used to examine the association between early-life tobacco smoke exposures and incident cataract. Additionally, the association between different types of tobacco smoke and cataract risk was also explored., Results: During a median follow-up of 12.04 years, 14,754 cases of incident cataract were documented. After adjusting confounders, the incidence of cataract significantly increased among participants with tobacco smoke exposures (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.09-1.18). Furthermore, individuals who were exposed to tobacco smoke in childhood (HR = 1.10, 95% CI = 1.03-1.21), adolescence (HR = 1.15, 95% CI = 1.10-1.21), and adulthood (HR = 1.12, 95% CI = 1.05-1.19) had an increased risk of cataract. Additionally, individuals who smoked cigars or pipes (HR = 1.26, 95% CI = 1.11-1.44), hand-rolled cigarettes (HR = 1.20, 95% CI = 1.05-1.36), and manufactured cigarettes (HR = 1.12, 95% CI = 1.08-1.17) were associated with an increased risk of cataract., Conclusions: Individuals with early-life tobacco smoke exposures in childhood and adolescence significantly elevate the risks of cataract incidence in older age., Translational Relevance: This study identified cataract-associated risks and suggested interventions like banning youth smoking to reduce future cataract incidence.

Cholangiocarcinoma is a malignant tumor that affects the bile ducts and is usually aggressive with poor prognosis. The treatment of cholangiocarcinoma depends on the stage and location of the tumor as well as the patient's overall health status. Systemic therapy, such as chemotherapy using gemcitabine and cisplatin, is the first choice for patients with cholangiocarcinoma who were inoperable. After no response to first-line chemotherapy, second-line chemotherapy or targeted therapy focusing on signaling pathway inhibition are subsequent treatment. The present report described a case of cholangiocarcinoma involving bilateral lobes of liver. He received one cycle of chemotherapy with gemcitabine plus cisplatin and exhibited rapid progression. Next-generation sequencing was performed, and the results showed that MET amplification had a gene copy number of 68. After that, he underwent tepotinib and tumor shrinkage occurred. After a follow‑up period of 12 months, the treatment response was partial response, and the benefit of tepotinib is ongoing. The development of precision medicine has expanded the paradigm of targeted therapies to increasingly favorable options in the second line and beyond, and prolong overall survival. Detecting druggable mutations (mutations potentially amenable to treatment with) for identifying a landscape of therapeutic options is imperative for managing cholangiocarcinoma., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Chen et al.)

The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8 + T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Morphology of right ventricular outflow tract (RVOT) is potentially related to cardiovascular outcomes. However, this relationship still remains to be verified with direct evidence. We retrospectively reviewed cases from the autopsy specimen library in the Center of Forensic Medicine in Sun Yat-sen University from 2017 to 2023. Six RVOT morphological characteristics were measured and their association with cardiovascular diseases (CVDs), sudden cardiac death (SCD) and age at death was evaluated. Relationship between myocardial fibrosis in RVOT and CVDs was investigated. RVOT characteristics were recruited by machine learning algorithms for diagnosing CVDs. A total of 2370 cases were finally recruited. Perimeter of sub-valve plane (pSBV) in RVOT was positively associated with risk of CVDs and SCD (OR: 1.21, 95%CI: 1.07-1.37, p = 0.003; OR: 1.33, 95%CI: 1.16-1.52, p < 0.001). Compared with thickness of septum (tS) < 3.0 mm, tS ≥ 3.0 mm was associated with premature death in disease-dominant death (β=-0.16, 95%CI: -0.20 to -0.11, p < 0.001) and SCD (β=-0.15, 95%CI: -0.21 to -0.10, p < 0.001). Degree of myocardial fibrosis in the posterior septum was increased in coronary atherosclerosis (6.86%±2.48% vs. 4.91%±2.14%, p = 0.011) and cardiomyopathies (8.11%±3.24% vs. 4.88%±3.11%, p = 0.005). A logistic regression model, recruiting age, left and right ventricular wall thickness, pSBV, circumference of pulmonary annulus and aortic annulus, was elected as an optimal diagnostic model of CVDs, yielding AUC of 0.734 (95%CI: 0.705-0.763), 0.781 (0.740-0.821) and 0.763 (0.725-0.800) in training, validation and test sets. Increased pSBV significantly correlates with higher risk of CVDs and SCD. And tS ≥ 3.0 mm is an independent risk factor of premature death regardless of diseases., (© 2024. The Author(s).)

Introduction: Spinal pain at night is a major contributor to the patient burden of radiographic axial spondyloarthritis (r-axSpA), resulting in substantial functional limitations and impairment of health-related quality of life (QoL). Ixekizumab (IXE), an interleukin-17A inhibitor, has shown efficacy in patients with r-axSpA., Objective: To assess spinal pain at night improvement up to week (W) 52 in COAST-V and to determine if clinically important improvement in spinal pain at night at W16 is associated with improvement in disease activity and other patient-reported outcomes (PROs) at W16 and W52., Methods: The 52 W phase 3 COAST-V trial investigated the efficacy of IXE in patients with r-axSpA that were naïve to biological disease-modifying anti-rheumatic drug (bDMARD). Patients were randomised to IXE every two weeks (Q2W), IXE every four weeks (Q4W), adalimumab (ADA) Q2W, or placebo up to W16. Patients were categorised as achieving or not achieving a ≥3-point improvement, considered a clinically important improvement (CII), in spinal pain at night at W16. Associations between achieving CII in spinal pain at night at W16 and change from baseline in disease activity (ASDAS, ASAS40), Fatigue severity NRS, JSEQ, WPAI and the SF-36 survey, were tested using analysis of covariance (continuous variables) and logistic regression (binary variables)., Results: At W16, 63.0 % (n=51), 46.7 % (n=42), and 32.2 % (n=28) of patients treated with IXE Q4W, ADA Q2W, and placebo, respectively, had reached a CII in spinal pain at night. Of those who were treated with IXE Q4W and achieved a CII in spinal pain at night at W16, 58.8 % and 66.7 % achieved an ASDAS <2.1 at W16 and W52 while 25.5 % and 29.4 % of patients also achieved ASDAS <1.3 at W16 and W52, respectively. Results at W16 and W52 show an improvement in disease activity, functioning, and health related QoL for patients who achieved a CII in spinal pain at night at W16., Conclusion: A larger proportion of patients treated with IXE Q4W achieved rapid and clinically meaningful improvement in spinal pain at night versus placebo, with improvements maintained up to W52. Achieving a CII in spinal pain at night at W16 was associated with improved disease activity, functioning, PROs, and QoL at W16 and W52., Trial Registration: ClinicalTrials.gov NCT02696785., Competing Interests: Declaration of competing interest Sofia Ramiro received grants from AbbVie, Galapagos, MSD, Novartis, Pfizer, and UCB, consulting fees from AbbVie, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Sanofi, and UCB, honoraria from AbbVie, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Sanofi, and UCB, support for attending meetings and travel from Eli Lilly and Company, and is an executive committee member at ASAS and a committee member at EULAR Quality of Care. Cédric Lukas received consulting fees from Abbvie, BMS, Pfizer, Roche Chugai, Janssen, UCB, and Eli Lilly and Company, honoraria from AbbVie, Pfizer, Celgene, UCB, and MSD, support for attending meeting and travel from Janssen, Pfizer, Abbvie, Celgene, and Eli Lilly and Company. Michael J Nissen received a grant from Novartis, consulting fees from Abbvie, Amgen, Eli Lilly and Company, Janssen, Novartis, and Pfizer, support for attending meetings and travel from Janseen and UCB, participated in data safety monitoring boards or advisory board for Eli Lilly and Company, Janssen, Novartis, and Pfizer, is a scientific member of the SCQM registry and the EuroSpA collaboration, and is an ASAS-EULAR taskforce member. Antoni Chan received a non-promotional educational grant from UCB, support for speaker bureau for Abbvie, UCB, Novartis, Janssen, and Medacs, honoraria from Eli Lilly and Company, meeting and travel support from UCB, Novartis, and Eli Lilly and Company, and participated in advisory board for Novartis and Abbvie. James Cheng-Chung Wei received honoraria from Pfizer, Abbvie, UCB, Chugai, and Novartis. Soyi Liu-Leage was an employee and shareholder at Eli Lilly and Company. Baojin Zhu, Khai Jing Ng, Mohamed Sheesh, Gabriel Doridot, and Ying Fang are Employee and shareholder at Eli Lilly and Company., (Copyright © 2024. Published by Elsevier Inc.)

The prevalence of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) and carbapenem-resistant Enterobacterales (CRE) has become a global public health problem. ESBL-E/CRE colonization can increase the risk of infection in patients and lead to poor disease prognosis. We conducted a systematic review and meta-analysis to evaluate current decolonization strategies regarding ESBL-E/CRE and their efficacy. A literature search was conducted until August 2023 on the five databases to review decolonization strategies associated with ESBL-E/CRE. A meta-analysis was conducted using RevMan 5.4 to compare differences in the decolonization strategy with placebo controls. The primary outcome was decolonization rates, with secondary outcomes of attributable death and adverse events. Quality of identified studies was determined using the Newcastle-Ottawa scale and cochrane risk assessment tool. Random and fixed effects meta-analyses were performed to calculate pooled value. A total of 25 studies were included. In five randomized controlled trial (RCT) studies, the decolonization effect of selective digestive decontamination(SDD) on ESBL-E/CRE at the end of treatment was significantly better in the experimental group than the controls [risk radio (RR): 3.30; 95% CI 1.78-6.14]. In three n-RCT studies, the decolonization effect in the experimental group was still better than the controls one month after SDD therapy [odds ratio (OR): 4.01; 95% CI 1.88-8.56]. The combined decolonization rates reported by six single-arm trial studies of SDD therapy ranged from 53.8 to 68.0%. Additionally, TSA analysis confirmed the effectiveness of SDD therapy. In studies on Faecal microbiota transplantation (FMT) therapy, the decolonization effect of the experimental group was significantly better than the controls 1 month after treatment (OR: 2.57; 95% CI 1.07-6.16). In studies without a control group and with varying follow-up times, the decolonization rates varied widely but indicated the effectiveness trend of FMT therapy (61.3-81.2%). Currently, research on the decolonization effect of probiotic therapy on ESBL-E/CRE is insufficient, and only a systematic review was conducted. SDD and FMT strategies have short-term benefits for ESBL-E/CRE decolonization, but long-term effects are unclear. The effect of probiotic therapy on ESBL-E/CRE decolonization is an interesting topic that still requires further investigation., (© 2024. The Author(s).)

Background: Delayed diagnosis and treatment of vision-threatening diabetic retinopathy (VTDR) is a common cause of visual impairment in individuals with type 2 diabetes mellitus (T2DM). Identification of VTDR predictors is the key to early prevention and intervention, but the predictors from previous studies are inconsistent. This study aims to conduct a systematic review and meta-analysis of the existing evidence for VTDR predictors, then to develop a risk prediction model after quantitatively summarising the predictors across studies, and finally to validate the model with two Chinese cohorts., Methods: We systematically retrieved cohort studies that reported predictors of VTDR in T2DM patients from PubMed, Ovid, Embase, Scopus, Cochrane Library, Web of Science, and ProQuest from their inception to December 2023. We extracted predictors reported in two or more studies and combined their corresponding relative risk (RRs) using meta-analysis to obtain pooled RRs. We only selected predictors with statistically significant pooled RRs to develop the prediction model. We also prospectively collected two Chinese cohorts of T2DM patients as the validation set and assessed the discrimination and calibration performance of the prediction model by the time-dependent ROC curve and calibration curve., Results: Twenty-one cohort studies involving 622 490 patients with T2DM and 57 107 patients with VTDR were included in the meta-analysis. Age of diabetes onset, duration of diabetes, glycosylated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), hypertension, high albuminuria and diabetic treatment were used to construct the prediction model. We validated the model externally in a prospective multicentre cohort of 555 patients with a median follow-up of 52 months (interquartile range = 39-77). The area under the curve (AUC) of the prediction model was all above 0.8 for 3- to 10-year follow-up periods and different cut-off value of each year provided the optimal balance between sensitivity and specificity. The data points of the calibration curves for each year closely surround the corresponding dashed line., Conclusions: The risk prediction model of VTDR has high discrimination and calibration performance based on validation cohorts. Given its demonstrated effectiveness, there is significant potential to expand the utilisation of this model within clinical settings to enhance the detection and management of individuals at high risk of VTDR., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Both artificially synthesized and naturally occurring cyclic chalcones have been widely studied for their excellent biological activities. However, research on its photophysical properties is still limited. In the present study, we designed and synthesized a small molecule fluorescent dye based on the ICT effect, using dimethylamino as the electron-donating group and carbonyl as the electron withdrawing group, and investigated its photophysical properties in depth. Although YB is a simple small molecule, it exhibits significant piezochromic properties. The fluorescence of YB can change from green to yellow through grinding. After solvent fumigation, the fluorescence reverts to green. Furthermore, YB was used successfully in the lysosomal targeting. This study expands the research on the photophysical properties of cyclic chalcone and give richness to application of cyclic chalcone compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Exposure to ambient ozone has been associated with extrapulmonary health, but the underlying mechanisms remain to be understood. LncRNAs are involved in the regulation of gene expression, but their regulatory mechanisms in ozone-related health effects are scarcely explored., Objective: To investigate genome-wide lncRNA changes after short-term ozone exposure and their regulatory roles in ozone exposure and gene expression., Method: We conducted a randomized, crossover, controlled exposure trial in 32 healthy college students in Shanghai, China. Each participant received both 200-ppb ozone exposure and filtered air exposure for 2 h in a random order with a 14-day washout period. Blood samples were collected after each exposure and used for lncRNA sequencing. Differentially expressed lncRNAs between the two exposures were identified using orthogonal partial least squares discriminant analysis and linear regression analysis. LncRNAs-targeted mRNAs were mapped and subjected to enrichment analyses. We also constructed lncRNA-miRNA-mRNA networks., Results: A total of 90 lncRNAs were differentially expressed after exposure to ozone, with 49 up-regulated and 41 down-regulated. Enrichment analyses suggested that these dysregulated lncRNAs were involved in a variety of biological processes, including those related to oxidative stress, inflammation response, and cell proliferation, development, and differentiation. Multiple pathways such as IL-17 signaling, NF-kB signaling, and Rho GTPases signaling were also enriched. Furthermore, the lncRNA-miRNA-mRNA network revealed that specific lncRNAs may regulate the expression of inflammation- and angiogenesis-related genes by interacting with miRNAs, such as NEAT1/hsa-miR-500a-3p/SIGLEC8, NEAT1/hsa-miR-6835-3p/SLC16A14, OIP5-AS1/miR-183-5p/EGR1, and SNHG25/hsa-miR-663a/FOSB axes., Conclusion: This study characterized a thorough profile of human lncRNAs following short-term ozone exposure and suggested the regulatory roles of these lncRNAs in ozone-induced inflammatory responses and angiogenesis, providing novel epigenetic insights into the mechanisms of the health effects of ozone exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate and compare the effectiveness of knowledge base-optimized and unoptimized large language models (LLMs) in the field of orthopedics to explore optimization strategies for the application of LLMs in specific fields., Methods: This research constructed a specialized knowledge base using clinical guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and authoritative orthopedic publications. A total of 30 orthopedic-related questions covering aspects such as anatomical knowledge, disease diagnosis, fracture classification, treatment options, and surgical techniques were input into both the knowledge base-optimized and unoptimized versions of the GPT-4, ChatGLM, and Spark LLM, with their generated responses recorded. The overall quality, accuracy, and comprehensiveness of these responses were evaluated by 3 experienced orthopedic surgeons., Results: Compared with their unoptimized LLMs, the optimized version of GPT-4 showed improvements of 15.3% in overall quality, 12.5% in accuracy, and 12.8% in comprehensiveness; ChatGLM showed improvements of 24.8%, 16.1%, and 19.6%, respectively; and Spark LLM showed improvements of 6.5%, 14.5%, and 24.7%, respectively., Conclusion: The optimization of knowledge bases significantly enhances the quality, accuracy, and comprehensiveness of the responses provided by the 3 models in the orthopedic field. Therefore, knowledge base optimization is an effective method for improving the performance of LLMs in specific fields., (© 2024. Huazhong University of Science and Technology.)

Objective: To evaluate the efficacy, safety, and improvement of symptoms by ultrasound-guided microwave ablation (MWA) for patients with large benign thyroid nodules (BTNs)., Methods: Eighty-seven patients with 87 BTNs (≥ 4 cm) treated with MWA between April 2015 and March 2021 were enrolled in this retrospective multicenter study, with clinical and ultrasound examinations performed at the 1st, 3rd, 6th, and 12th months. A multivariable linear mixed effects model was employed to explore the alterations in volume and volume reduction ratio (VRR), as well as the potential factors associated with VRR., Results: The mean age of the 87 patients was 45.69 ± 14.21 years (range 18-76 years), and the ratio of men to women was 1:4.8. The mean volumes were much decreased at the 12th month after ablation compared to the initial volumes (p < .001). The mean VRR was 76.09% at the 12th month. The technique efficacy (VRR > 50%) was 90.80% at the 12th month. A multivariate analysis revealed that VRR was related to the initial volume (p = .015), annular flow (p = .010), and nodule composition (p = .024). The mean symptomatic score decreased from 4.40 ± 0.28 to 0.26 ± 0.06 at the 12th month (p < .001). At the same time, the mean cosmetic score decreased from 3.22 ± 0.10 to 1.31 ± 0.08 (p < .001)., Conclusion: MWA could serve as a safe and effective therapy for large BTNs, significantly reducing the volume of BTNs and significantly improving compressive symptoms and appearance problems., Clinical Relevance Statement: Microwave ablation could serve as a safe and effective therapy for large benign thyroid nodules, leading to significant volume reduction and satisfied symptom and cosmetic alleviation period., Key Points: • This multicenter study investigated the feasibility and safety of microwave ablation for large benign thyroid nodules. • After ablation, the nodule volume was significantly reduced, and patients' symptoms and appearance problems were significantly improved. • Microwave ablation is feasible for large benign thyroid nodules and has been a supplement treatment., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: To evaluate the long-term efficacy of once-daily baricitinib 4 mg or 2 mg in patients with active rheumatoid arthritis who had inadequate response (IR) to MTX, csDMARDs or bDMARDs., Methods: Data from three completed phase III studies-RA-BEAM (MTX-IR), RA-BUILD (csDMARD-IR) and RA-BEACON (bDMARD-IR)-and one completed long-term extension study (RA-BEYOND) were analysed up to 6.5 years [340 weeks (RA-BEAM) and 336 weeks (RA-BUILD and RA-BEACON)]. Low disease activity (LDA) [Simplified Disease Activity Index (SDAI) ≤11], clinical remission (SDAI ≤3.3) and physical function [Health Assessment Questionnaire Disability Index (HAQ-DI) ≤0.5] were the main outcomes assessed. Completer and non-responder imputation (NRI) analyses were conducted on each population., Results: At week 340 or 336, LDA was achieved in 37%/83% of MTX-IR, 35%/83% of csDMARD-IR and 23%/73% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. Remission was achieved in 20%/40% of MTX-IR, 13%/32% of csDMARD-IR and 9%/30% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. HAQ-DI ≤0.5 was reached in 31%/51% of MTX-IR, 25%/46% of csDMARD-IR and 24%/38% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively., Conclusion: Treatment with baricitinib 4 mg or 2 mg demonstrated efficacy up to 6.5 years with maintained LDA/remission results across SDAI, CDAI and DAS28-hsCRP consistent with previously reported data, and was well tolerated., Trial Registration: United States National Library of Medicine clinical trials database www.clinicaltrials.gov; RA-BEYOND; NCT01885078., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Cataract is a leading cause of blindness worldwide. However, little is known about sex differences in cataracts. Our study aimed to explore potential sex differences in the relationships between key social, lifestyle, and physical health risk factors and the incidence of cataracts., Methods: A total of 117,972 participants from the UK Biobank were included in this prospective cohort study. Cox proportional hazard models were used to calculate hazard ratios (HRs) and female-to-male ratios of HRs (RHRs) with 95% confidence intervals (CIs) for cataract risk factors. Poisson regression was used to assess the incidence of cataracts (per 10,000 person-years)., Results: A total of 117,972 individuals without preexisting eye diseases were enroled in the analysis. 4172 subjects (54.8% female) were diagnosed with cataracts during follow-up. The crude incidence rates per 10,000 person-years were 35.06 for females and 29.15 for males. The incidence of cataracts increased in both males and females with factors such as Asian or Black ethnicity, smoking status, obesity, diabetes, and myopia. However, males who consumed alcohol or were unemployed suffered a greater risk of cataracts compared to their female counterparts, while high socioeconomic status, elevated blood pressure and metabolic syndrome were associated with a greater risk of cataracts in females than in males., Conclusion: This study provides a comprehensive overview of sex differences in the associations between cataracts and various risk factors. Our findings highlight that socioeconomic and lifestyle risk factors are more strongly linked to cataract risk in males, whereas females with systemic diseases face a greater risk of developing cataract., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Fusarium head blight (FHB), caused by Fusarium graminearum, is a devastating disease of wheat globally. However, the molecular mechanisms underlying the interactions between F. graminearum and wheat remain unclear. Here, we identified a secreted effector protein, FgEC1, that is induced during wheat infection and is required for F. graminearum virulence. FgEC1 suppressed flg22- and chitin-induced callose deposition and reactive oxygen species (ROS) burst in Nicotiana benthamiana. FgEC1 directly interacts with TaGF14b, which is upregulated in wheat heads during F. graminearum infection. Overexpression of TaGF14b increases FHB resistance in wheat without compromising yield. TaGF14b interacts with NADPH oxidase respiratory burst oxidase homolog D (TaRBOHD) and protects it against degradation by the 26S proteasome. FgEC1 inhibited the interaction of TaGF14b with TaRBOHD and promoted TaRBOHD degradation, thereby reducing TaRBOHD-mediated ROS production. Our findings reveal a novel pathogenic mechanism in which a fungal pathogen acts via an effector to reduce TaRBOHD-mediated ROS production., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Introduction: Blunt cardiac injury (BCI), associated with high morbidity and mortality, involves multiple injuries. With no widely accepted gold standard diagnostic test and molecular biomarkers still in debate and far from application in clinical practice, exploring specific molecular biomarkers of BCI is of great significance. The clarification of molecular biomarkers can improve the diagnosis of BCI, leading to more precise care for victims in various situations., Areas Covered: Using the search term 'Biomarker AND Blunt cardiac injury,' we carefully reviewed related papers from June 2004 to June 2024 in PubMed and CNKI. After reviewing, we included 20 papers, summarizing the biomarkers reported in previous studies, and then reviewed molecular biomarkers such as troponins, Nterminal proBtype natriuretic peptide (NT proBNP), hearttype fatty acid binding protein (hFABP), and lactate for BCI diagnosis. Finally, valuable views on future research directions for diagnostic biomarkers of BCI were presented., Expert Opinion: Several advanced technologies have been introduced into clinical medicine, which have ultimately changed the research on cardiac diseases in recent years. Some biomarkers have been identified and utilized for BCI diagnosis. Herein, we summarize the latest relevant information as a reference for clinical practice and future studies.

Background: Fever is a common side effect following thermal ablation in patients with hepatocellular carcinoma (HCC), yet its impact on prognosis remains unclear., Materials and Methods: This retrospective study included initial HCC patients who underwent US-guided percutaneous microwave ablation at 13 hospitals between January 2006 and February 2021. All patients were categorized into afebrile, transient low-grade fever (TLF), and prolonged or high-grade fever (PHF) groups. Primary outcomes included very early recurrence (VER) and early recurrence (ER), secondary outcomes were disease-free survival (DFS) and overall survival (OS). Fever cut-offs for VER/ER were established using restrictive cubic splines and adjusted Cox model. Survival analyses used the Kaplan-Meier method., Results: A total of 1458 initial HCC patients (mean age, 59±11[SD]; 1146 men). Compared to afebrile individuals, patients with TLF (temperatures ranging 37.0-38.8°C for 1-2 d), showed independent protective effects against VER (HR, 0.73; 95% CI: 0.57,0.95; P=0.02) and ER (HR, 0.66; 95% CI: 0.54,0.81; P<0.001), however, PHF showed no differences in VER (HR, 0.99; 95% CI: 0.76,1.30; P=0.96) and ER (HR, 0.86; 95% CI: 0.69,1.07; P=0.17). With a median follow-up of 47 months (IQR:26-79), the median DFS for TLF patients was 40 months, superior to afebrile (30 mo, P=0.019) and PHF patients (33 mo, P=0.049). The 5-year OS rate for TLF patients was 73.2%, higher than afebrile (69.3%, P=0.02) and PHF patients (66.7%, P=0.03). No significant difference was found in DFS and OS between afebrile and PHF patients (P=0.90 and 0.71). Notably, TLF patients exhibited the highest lymphocyte counts increasing median 7 days after ablation (P<0.001 vs. afebrile and P=0.01 vs. PHF)., Conclusion: Transient low-grade fever following percutaneous microwave ablation in hepatocellular carcinoma patients demonstrated protection against early recurrence, possibly attributed to the short-term activation of lymphocytes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved., Methods: The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2) ., Results: The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway., Conclusion: PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease.

Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC-1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC-1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC's resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: This study aims to establish a predictive model for assessing the risk of esophageal cancer lung metastasis using machine learning techniques., Methods: Data on esophageal cancer patients from 2010 to 2020 were extracted from the surveillance, epidemiology, and end results (SEER) database. Through univariate and multivariate logistic regression analyses, eight indicators related to the risk of lung metastasis were selected. These indicators were incorporated into six machine learning classifiers to develop corresponding predictive models. The performance of these models was evaluated and compared using metrics such as The area under curve (AUC), accuracy, sensitivity, specificity, and F1 score., Results: A total of 20,249 confirmed cases of esophageal cancer were included in this study. Among them, 14,174 cases (70%) were assigned to the training set while 6075 cases (30%) constituted the internal test set. Primary site location, tumor histology, tumor grade classification system T staging criteria N staging criteria brain metastasis bone metastasis liver metastasis emerged as independent risk factors for esophageal cancer with lung metastasis. Amongst the six constructed models, the GBM algorithm-based machine learning model demonstrated superior performance during internal dataset validation. AUC, accuracy, sensitivity, and specificity values achieved by this model stood at respectively at 0.803, 0.849, 0.604, and 0.867., Conclusion: We have developed an online calculator based on the GBM model ( https://lvgrkyxcgdvo7ugoyxyywe.streamlit.app/)to aid clinical decision-making and treatment planning., (© 2024. The Author(s).)

Background: In-depth understanding of dynamic expression profiles of human granulosa cells (GCs) during follicular development will contribute to the diagnostic and targeted interventions for female infertility. However, genome-scale analysis of long non-coding ribonucleic acid (lncRNA) in GCs across diverse developmental stages is challenging. Meanwhile, further research is needed to determine how aberrant lncRNA expression participates in ovarian diseases., Methods: Granulosa cell-related lncRNAs data spanning five follicular development stages were retrieved and filtered from the NCBI dataset (GSE107746). Stage-specific lncRNA expression patterns and mRNA-lncRNA co-expression networks were identified with bioinformatic approaches. Subsequently, the expression pattern of SNHG18 was detected in GCs during ovarian aging. And SNHG18 siRNA or overexpression plasmids were transfected to SVOG cells in examining the regulatory roles of SNHG18 in GC proliferation and apoptosis. Moreover, whether PKCɛ/SNHG18 signaling take part in GC glycolysis via ENO1 were verified in SVOG cells., Results: We demonstrated that GC-related lncRNAs were specifically expressed across different developmental stages, and coordinated crucial biological functions like mitotic cell cycle and metabolic processes in the folliculogenesis. Thereafter, we noticed a strong correlation of PRKCE and SNHG18 expression in our analysis. With downregulated SNHG18 of GCs identified in the context of ovarian aging, SNHG18 knockdown could further induce cell apoptosis, retard cell proliferation and exacerbate DNA damage in SVOG cell. Moreover, downregulated PKCɛ/SNHG18 pathway interrupted the SVOG cell glycolysis by lowering the ENO1 expression., Conclusions: Altogether, our results revealed that folliculogenesis-related lncRNA SNHG18 participated in the pathogenesis of ovarian aging, which may provide novel biomarkers for ovarian function and new insights for the infertility treatment., (© 2024. The Author(s).)

Hydrogen sulfide (H 2 S) is a gaseous signaling molecule that regulates various physiological and pathological processes in the central nervous system. It is vital to develop an effective method to detect H 2 S in vivo to elucidate its critical role. However, current fluorescent probes for accurate quantification of H 2 S still face big challenges due to complicated fabrication, small Stokes shift, unsatisfactory selectivity, and especially delayed response time. Herein, based on simple postsynthetic modification, we present an innovative strategy by confining H 2 S-triggered thiolysis of dinitrophenyl (DNP) ether within a luminescent metal-organic framework (MOF) to address those issues. Due to the cleavage of the DNP moiety by H 2 S, the nanoprobe gives rise to a remarkable fluorescence turn-on signal with a large Stokes shift of 190 nm and also provides high selectivity to H 2 S against various interferents including competing biothiols. In particular, by virtue of the unique structural property of the MOF, it exhibits an ultrafast sensing ability for H 2 S (only 5 s). Moreover, the fluorescence enhancement efficiency displays a good linear correlation with H 2 S concentration in the range of 0-160 μM with a detection limit of 0.29 μM. Importantly, these superior sensing performances enable the nanoprobe to measure the basal value and monitor the change of H 2 S level in the rat brain.

Background: This study aims to analyze the efficacy and safety of neoadjuvant programmed cell death-1 (PD-1) blockade plus chemotherapy in real-world applications. Additionally, we report survival outcomes with a median follow-up of 40.1 months., Methods: From January 2018 to October 2022, we retrospectively recruited patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after receiving PD-1 blockade (immunotherapy) plus chemotherapy at Jiangsu Cancer Hospital., Results: A total of 132 eligible ESCC patients were included, and R0 resection was achieved in 131 cases (99.2 %). A complete pathological response rate (ypT0N0) was observed in 32 patients (24.2 %), and the objective response rate was 59.1 %. The most common grade 3-4 treatment-related adverse events (TRAEs) were leukopenia (18.2 %) and neutropenia (15.9 %). Three cases (2.3 %) of grade 3 immune-related AEs were observed, including increased ALT (0.8 %), rash (0.8 %), and encephalitis (0.8 %). The 1-year disease-free survival (DFS) and overall survival (OS) rates were 68.2 % and 89.4 %, respectively, and the 2-year DFS and OS rates were 55.1 % and 78.6 %, respectively. The pathological responses of 103 cases (94.5 % of 109) of the index lymph node (ILN) were categorized as the worst regression subgroup. In these cases, using the pathological response of the ILN to indicate the status of other lymph nodes would not result to a missed therapeutic lymph node dissection., Conclusions: Neoadjuvant immunotherapy plus chemotherapy is safe and effective for ESCC, with observable survival benefits. The pathological response of the ILN after neoadjuvant therapy may have important value in guiding therapeutic lymph node dissection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

We report the design, development, and characterization of a miniaturized version of the photonic resonator absorption microscope (PRAM Mini), whose cost, size, and functionality are compatible with point-of-care (POC) diagnostic assay applications. Compared to previously reported versions of the PRAM instrument, the PRAM Mini components are integrated within an optical framework comprised of an acrylic breadboard and plastic alignment fixtures. The instrument incorporates a Raspberry Pi microprocessor and Bluetooth communication circuit board for wireless control and data connection to a linked smartphone. PRAM takes advantage of enhanced optical absorption of ∼80 nm diameter gold nanoparticles (AuNP) whose localized surface plasmon resonance overlaps with the ∼625 nm resonant reflection wavelength of a photonic crystal (PC) surface. When illuminated with wide-field low-intensity collimated light from a ∼617 nm wavelength red LED, each AuNP linked to the PC surface results in locally reduced reflection intensity, which is visualized by observing dark spots in the PC-reflected image with an inexpensive CMOS image sensor. Each AuNP in the image field of view can be easily counted with digital resolution. We report upon the selection of optical/electronic components, image processing algorithm, and contrast achieved for single AuNP detection. The instrument is operated via a wireless connection to a linked mobile device using a custom-developed software application that runs on an Android smartphone. As a representative POC application, we used the PRAM Mini as the detection instrument for an assay that measures the presence of antibodies against SARS-CoV-2 infection in cat serum samples, where each dark spot in the image represents a complex between one immobilized viral antigen, one antibody molecule, and one AuNP tag. With dimensions of 23 × 21 × 10 cm 3 , the PRAM Mini offers a compact detection instrument for POC diagnostics., Competing Interests: B. Cunningham is a founder of Atzeyo Biosensors, which holds a license for the PRAM technology., (© 2024 Optica Publishing Group.)

Background: Central obesity was considered as a risk factor for falls among the older population. Waist circumference (WC), lipid accumulation product (LAP), visceral adiposity index (VAI), and the Chinese visceral adiposity index (CVAI) are considered as surrogate markers for abdominal fat deposition in increasing studies. Nevertheless, the longitudinal relationship between these indices and falls among the older population remains indistinct. This study aimed to explore the association between abdominal obesity indices and falls among older community-dwellers., Methods: Our study included 3501 individuals aged ≥ 65 years from the Guangzhou Falls and Health Status Tracking Cohort at baseline in 2021 and then prospectively followed up in 2022. The outcome of interest was the occurrence of falls. The Kaplan-Meier curves and multivariable Cox regression analysis were used to explore the associations between abdominal obesity indices and falls. Moreover, the restricted cubic spline analysis (RCS) was conducted to test the non-linear relationships between abdominal obesity indices and hazards of falls incident., Results: After a median follow-up period of 551 days, a total of 1022 participants experienced falls. The cumulative incidence rate of falls was observed to be higher among individuals with central obesity and those falling within the fourth quartile (Q4) of LAP, VAI, and CVAI. Participants with central obesity and those in Q4 of LAP, VAI, and CVAI were associated with higher risk of falls, with hazard ratios (HRs) of 1.422 (HR 95%CI: 1.255-1.611), 1.346 (1.176-1.541), 1.270 (1.108-1.457), 1.322 (1.154-1.514), respectively. Each 1-SD increment in WC, LAP, VAI, and CVAI was a significant increased risk of falls among participants. Subgroup analysis further revealed these results were basically stable and appeared to be significantly stronger among those females, aged 65-69 years, and with body mass index (BMI) ≥ 28 kg/m 2 . Additionally, RCS curves showed an overall upward trend in the risk of falls as the abdominal indices increased., Conclusions: Abdominal obesity indices, as WC, LAP, VAI, and CVAI were significantly associated with falls among older community-dwellers. Reduction of abdominal obesity indices might be suggested as the strategy of falls prevention., (© 2024. The Author(s).)

The transfer of arsenic (As) from soil to plant could be significantly influenced by soil parameters through regulating soil As bioavailability. To distinguish the bioavailable As provided by soil and the As uptaken by plants, herein two different soil bioavailable were defined, namely potential soil bioavailable As (evaluated through the bioavailable fraction of As) and actual soil bioavailable As (assessed through plant bioaccumulation factor, BF, and BF available ). To identify the dominant soil parameters for the two soil bioavailable As forms, soil and plant samples were collected from a former As mine site. The results showed that the potential bioavailable As only accounted for 1.77 to 11.43% in the sampled soils, while the BF and BF available in the sampled vegetables ranged from 0.00 to 1.01 and 0.01 to 17.87, respectively. Despite a similar proportion of As in the residual fraction, soil with higher pH and organic matter (OM) content and lower iron (Fe) content showed a higher potential soil bioavailable As. Correlation analysis indicated a relationship between the soil pH and potential soil bioavailable As (r = 0.543, p < 0.01) and between the soil Fe and actual soil bioavailable As (r =  - 0.644, p < 0.05, r =  - 0.594, p < 0.05). Stepwise multiple linear regression (SMLR) analysis was employed to identify the dominant soil parameters and showed that soil pH and phosphorus (P) content could be used to predict the potential soil bioavailable As (R 2  = 0.69, p < 0.001). On the other hand, soil Fe and OM could be used to predict the actual soil bioavailable As (R 2  = 0.18-0.86, p < 0.001-0.015, in different vegetables). These results suggest that different soil parameters affect potential and actual soil bioavailable As. Hence, soil Fe and OM are the most important parameters controlling As transfer from soil to plant in the investigated area., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The demand for telesurgery is rapidly increasing. Augmented reality (AR) remote surgery is a promising alternative, fulfilling a worldwide need in fracture surgery. However, previous AR endoscopic and Google Glass remotes remain unsuitable for fracture surgery, and the application of remote fracture surgery has not been reported. The authors aimed to evaluate the safety and clinical effectiveness of a new AR remote in fracture surgery., Materials and Methods: This retrospective non-inferiority cohort study was conducted at three centres. Between 1 January 2018 and 31 March 2022, 800 patients who underwent fracture surgery were eligible for participation. The study enroled 551 patients with fractures (132 patellae, 128 elbows, 126 tibial plateaus, and 165 ankles) divided into an AR group (specialists used AR to remotely guide junior doctors to perform surgeries) and a traditional non-remote group (specialists performed the surgery themselves)., Results: Among 364 patients (182 per group) matched by propensity score, seven (3.8%) in the AR group and six (3%) in the non-remote group developed complications. The 0.005 risk difference (95% CI: -0.033 to 0.044) was below the pre-defined non-inferiority margin of a 10% absolute increase. A similar distribution in the individual components of all complications was found between the groups. Hierarchical analysis following propensity score matching revealed no statistical difference between the two groups regarding functional results at 1-year follow-up, operative time, amount of bleeding, number of fluoroscopies, and injury surgery interval. A Likert scale questionnaire showed positive results (median scores: 4-5) for safety, efficiency, and education., Conclusion: This study is the first to report that AR remote surgery can be as safe and effective as that performed by a specialist in person for fracture surgery, even without the physical presence of a specialist, and is associated with improving the skills and increasing the confidence of junior surgeons. This technique is promising for remote fracture surgery and other open surgeries, offering a new strategy to address inadequate medical care in remote areas., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety. In this review, we discuss the mechanisms by which CAR-T cells target autoimmune conditions, summarize current preclinical models, and highlight ongoing clinical trials, including CAR-T therapy design, clinical outcomes, and challenges. Additionally, we discuss the limitations and future directions of CAR-T therapy in the treatment of autoimmune diseases., Competing Interests: Declaration of interests We declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aims to evaluate the instructional efficacy of a 3D Surgical Training System (3DSTS), which combines real surgical footage with high-definition 3D animations, against conventional surgical videos and textbooks in the context of orthopedic proximal humerus fracture surgeries., Design: Before the experiment, 89 participants completed a pre-educational knowledge assessment. They were then randomized into 3 groups: the 3DSTS group (n = 30), the surgical video (SV) group (n = 29), and the textbook group (n = 30). After their respective teaching courses, all participants took a posteducational assessment and completed a perceived cognitive load test. The 3DSTS group also filled out a satisfaction survey. Once all assessments were finished, the SV and textbook groups were introduced to the 3DSTS course and subsequently completed a satisfaction survey. All statistical analyses were executed using IBM SPSS version 24 (IBM Corp., Armonk, NY). For data fitting normal distribution, we employed one-way analysis of variance (one-way ANOVA) and Tukey HSD tests, whereas, for non-normally distributed data, we used Kruskal-Wallis H tests and Dunn's tests. The significance level for all tests was set at p < 0.05., Setting: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China., Participants: About 89 doctors who undergoing standardized residents training., Result: The initial assessment scores among the three groups were comparable, showing no significant statistical difference. Post-education revealed a marked difference in the scores, with the 3DSTS group outperforming both the SV and textbook groups. Specifically, the 3DSTS group exhibited statistically greater improvement in areas such as procedural steps, and specialized surgical techniques compared to the SV and textbook groups. During the 3DSTS teaching process, participants reported the least perceived cognitive load and expressed strong satisfaction, highlighting that the instructional materials are well-prepared, and considering this teaching method superior and more innovative than previous courses they had encountered., Conclusion: The 3D Surgical Training System, integrating real videos with 3D animations, significantly enhances orthopedic surgery education over conventional methods, providing improved comprehension, lower cognitive load, and standardized learning outcomes. Its efficacy and high participant satisfaction underscore its potential for broader adoption in surgical disciplines. This study is registered with ClinicalTrials. gov ID: ChiCTR2300074730., (Copyright © 2024. Published by Elsevier Inc.)

We aimed to explore the efficacy of rechallenge after first-line immunotherapy in advanced gastric cancer (AGC) and to analyze the factors affecting prognosis based on clinical characteristics. Eighty-five AGC patients who underwent rechallenged after the failure of first-line treatment with immune checkpoint inhibitors (ICIs) were retrospectively collected from July 2019 to December 2022 in Jiangsu Cancer Hospital. Potential factors affecting prognosis were analyzed by univariate and multivariate Cox analysis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Stratified factors included human epidermal growth factor receptor 2 (HER-2) and programmed cell death-ligand 1 combined positive score (PD-L1 CPS). The objective response rate (ORR) was 15.3%, and the disease control rate (DCR) was 74.1%. The median progression-free survival (PFS) was 4.8 months. Results showed that patients in the I + C group had the best response. The ORR was 20.0% VS 8.7% in the I + C group and I + C + AAD group. The DCR was 78.0% VS 65.2%, and the median PFS was 6.7 VS 4.7 months [hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.30-1.00, p  = .022]. The ORR was 20.0% VS 8.3% in the I + C group and I + C + ADC group. The DCR was 78.0% VS 75.0%, and the median PFS was 6.7 VS 4.4 months (HR: 0.59, 95%CI: 0.26-1.30, p  = .112). The median PFS was 4.7 VS 4.4 months in the I + C + AAD group and I + C + ADC group (HR: 1.21, 95%CI: 0.60-2.47, p  = .580). Adverse events (AEs) were found in 34 patients, mainly including leukopenia 9 (10.6%), and neutropenia 8 (9.4%). The incidence of grade 3-4 AEs was 8.2%. There were no drug-related deaths and all AEs were manageable. Rechallenge after first-line immunotherapy showed good survival benefit and acceptable safety in the therapy of AGC. Especially for patients with HER-2-positive and PD-L1 CPS ≥ 1%, rechallenge may be an effective treatment modality.

Objective: Explore the efficacy and safety of involved-field irradiation (IFI) combined with S-1 as definitive concurrent chemoradiotherapy (dCRT) for locally advanced elderly esophageal squamous cell carcinoma (ESCC), under the premise of intensity-modulated radiotherapy (IMRT)., Methods: We designed a prospective single-arm phase II study. The study enrolled 91 patients aged 75 to 92 years. Eligible participants had histologically confirmed squamous cell carcinoma, stage II to IV disease based on the 8th edition of the American Joint Committee on Cancer (AJCC). All elderly patients (EPs) received dCRT with S-1. which was administered orally twice daily for 28 days. The radiotherapy dose was 61.2 Gy delivered in 34 fractions or 50.4 Gy delivered in 28 fractions. The primary endpoint was 2-year overall survival (OS), and the secondary endpoints were progression-free survival (PFS), local control rate (LCR), and safety., Results: From July 2017 to July 2021, we enrolled EPs with ESCC who were treated at the Jiangsu Cancer hospital. As of August 1, 2023, the median follow-up of surviving EPs was 31.4 months (IQR: 25.2 to 72.6 months). 83 patients (91.2%) completed the whole course of treatment. The 2-year OS rate was 59.2%, and the PFS rate was 43.7%. The most common grade 1 to 2 adverse effects (AEs) were radiation esophagitis (79.1%), and then were radiation pneumonia (46.2%). Anemia (41.8%) was the most common of grade 1 to 2 hematologic toxicity. The incidence of grade 3 or above AEs was 24.2%, and the incidence of leukopenia was the highest (11.0%). There was not one death due to treatment-related toxicity. In a subgroup analysis of radiotherapy doses, we found no statistically significant differences in PFS (P = 0.465) and OS (P = 0.345) in EPs with ESCC who received 50.4 Gy and 61.2 Gy, and that patients in the 50.4 Gy group had lower dermatitis (P = 0.045) and anemia (P = 0.004)., Conclusions: IF-IMRT combined with S-1 is a promising regimen for elderly ESCC. And the radiotherapy dose of 50.4 Gy remains the standard dose for EPs with ESCC undergoing CCRT., (© 2024. The Author(s).)

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. However, the pathogenesis of GPP has not been fully elucidated. Although RNA-binding proteins (RBPs) and the alternative splicing (AS) process are essential for regulating post-transcriptional gene expression, their roles in GPP are still unclear. We aimed to elucidate the regulatory mechanisms to identify potential new therapeutic targets. Here, We analyzed an RNA sequencing (RNA-seq) dataset (GSE200977) of peripheral blood mononuclear cells (PBMCs) of 24 patients with GPP, psoriasis vulgaris (PV), and healthy controls (HCs) from the Gene Expression Omnibus (GEO) database. We found that the abnormal alternative splicing (AS) events associated with GPP were mainly "alt3p/alt5p", and 15 AS genes were differentially expressed. Notably, the proportions of different immune cell types were correlated with the expression levels of regulatory alternatively spliced genes (RASGs): significant differences were observed in expression levels of DTD2, NDUFAF3, NBPF15, and FBLN7 in B cells and ARFIP1, IPO11, and RP11-326L24.9 in neutrophils in the GPP samples. Furthermore, We identified 32 differentially expressed RNA-binding proteins (RBPs) (18 up-regulated and 14 down-regulated). Co-expression networks between 14 pairs of differentially expressed RBPs and RASGs were subsequently constructed, demonstrating that these differentially expressed RBPs may affect the progression of GPP by regulating the AS of downstream immune/inflammatory-related genes such as LINC00989, ENC1 and MMP25-AS1. Our results were innovative in revealing the involvement of inflammation-related RBPs and RASGs in the development of GPP from the perspective of RBP-regulated AS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ulcerative colitis (UC) is a chronic inflammatory disease, the incidence of which is increasing worldwide. However, the etiology and pathogenesis of UC remains unclear. The n-butanol extract of Pulsatilla decoction (BEPD), a traditional Chinese medicine, has been shown to be effective in treating UC. This study aimed to explore the molecular mechanism underlying the effects of BEPD on UC, in particular its effects on neutrophil extracellular trap (NET) formation by neutrophils. High-performance liquid chromatography was used to determine the principal compounds of BEPD. UC was induced in mice using dextran sodium sulfate, and mice were treated with 20, 40, or 80 mg/kg BEPD daily for seven days. Colonic inflammation was determined by assessing the disease activity index, histopathology, colonic mucosal damage index, colonic mucosal permeability, and pro- and anti-inflammatory cytokine levels. The infiltration and activation status of neutrophils in the colon were determined by analyzing the levels of chemokine (C-X-C motif) ligand (CXCL) 1 and CXCL2, reactive oxygen species, Ly6G, and numerous NET proteins. The findings suggest that BEPD improved the disease activity index, histopathology, and colonic mucosal damage index scores of mice with UC, and restored colonic mucosal permeability compared with untreated mice. The expression levels of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α in colon tissues were significantly decreased, while the expression levels of anti-inflammatory cytokines in colon tissues were significantly increased, exceeding those of control mice. In addition, BEPD reduced the expression of the neutrophil chemokines CXCL1 and CXCL2 in the colon tissue of mice with UC, reduced neutrophil infiltration, reduced reactive oxygen species levels, and significantly reduced the expression of NET proteins. BEPD also significantly reduced NET formation. The results of this study suggest that BEPD exerts therapeutic effects in a murine model of UC by inhibiting neutrophil infiltration and activation in the colon, as well as by inhibiting the expression of key proteins involved in NET formation and reducing NET formation, thereby alleviating local tissue damage and disease manifestations.

α-Glucosidase, which directly involves in the metabolism of starch and glycogen and causes an increase in blood sugar level, is the major target enzyme for the precaution and therapy of type II diabetes. Based on the previous work, we adopted a post-synthetic modification method to encapsulate Tb 3+ into Ce-MOF nanozyme which owned mixed valence states. Tb@Ce-MOF displayed induced luminescence characteristic and exceptional oxidase-like activity that could oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue ox-TMB. α-Glucosidase can hydrolyze the substrate l-ascorbic acid-2-O-α-d-glucopyranosyl (AAG) to generate ascorbic acid (AA), which could increase the Ce 3+ /Ce 4+ redox valence mode in Tb@Ce-MOF, leading to the inhibition of the allochroic reaction of TMB and the decreased absorption of ox-TMB at 652 nm. The energy transfer (EnT) process from Ce 3+ to Tb 3+ will enhance due to the increased Ce 3+ /Ce 4+ mode in Tb@Ce-MOF, which will result in an enhanced fluorescence signal of Tb@Ce-MOF at 550 nm. But the addition of inhibitor acarbose will inhibit the above process. We have constructed a dual-mode detection platform of α-glucosidase and its inhibitor via colorimetric and fluorometric method. The linear range of α-glucosidase were 0.01-0.5 U/mL (colorimetric mode) and 0.8-1.5 U/mL (fluorometric mode), respectively, with a detection limit as low as 0.0018 U/mL. Furthermore, our approach was also successfully employed to the analysis of α-glucosidase in serum samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Breast cancer presents significant challenges due to the limited effectiveness of available treatments and the high likelihood of recurrence. iRGD possesses both RGD sequence and C-terminal sequence and has dual functions of targeting and membrane penetration. iRGD-modified nanocarriers can enhance drug targeting of tumor vascular endothelial cells and penetration of new microvessels, increasing drug concentration in tumor tissues., Methods: The amidation reaction was carried out between SiO 2 /AuNCs and iRGD/PTX, yielding a conjugated drug delivery system (SiO 2 /AuNCs-iRGD/PTX, SAIP@NPs). The assessment encompassed the characterization of the morphology, particle size distribution, physicochemical properties, in vitro release profile, cytotoxicity, and cellular uptake of SAIP@NPs. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed using a small animal in vivo imaging system and a tumor-bearing nude mice model, respectively. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed utilizing a small animal in vivo imaging system and an in situ nude mice breast cancer xenograft model, respectively., Results: The prepared SAIP@NPs exhibited decent stability and a certain slow-release effect in phosphate buffer (PBS, pH 7.4). In vitro studies had shown that, due to the dual functions of transmembrane and targeting of iRGD peptide, SAIP@NPs exhibited strong binding to integrin αvβ3, which was highly expressed on the membrane of MDA-MB-231 cells, improving the uptake capacity of tumor cells, inhibiting the rapid growth of tumor cells, and promoting tumor cell apoptosis. The results of animal experiments further proved that SAIP@NPs had longer residence time in tumor sites, stronger anti-tumor effect, and no obvious toxicity to major organs of experimental animals., Conclusion: The engineered SAIP@NPs exhibited superior functionalities including efficient membrane permeability, precise tumor targeting, and imaging, thereby significantly augmenting the therapeutic efficacy against breast cancer with a favorable safety profile., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Hou et al.)

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANT→HPC/PMC→OFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: The gastrointestinal tract is a well-known extranodal site of lymphoma. B-cell lymphoma is the most common type, while T-cell lymphoma is uncommon. Primary gastrointestinal lymphoma mainly occurs in the stomach and small intestine, and the colon is less frequently involved, especially in females., Case Summary: A 45-year-old woman was admitted to our hospital for physical examination. Gastroenteroscopy revealed a visible pedunculated polyp in the transverse colon, for which endoscopic submucosal dissection (ESD) was performed. Pathology suggested highly active proliferation of T lymphocytes with atypical hyperplasia., Conclusion: A middle-aged female patient was found to have colonic T-cell lymphoma by endoscopy. The lesion was successfully removed by ESD, and the surgical margin was negative. It is essential to raise awareness of colonic T-cell lymphoma and choose the appropriate treatment., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Development of high-performance joint injection lubricants has become the focus in the field of osteoarthritis treatment. Herein, natural product of angelica essential oil combined with the graphene oxide were prepared to the stable Pickering emulsion as a biological lubricant. The tribological properties of the Pickering emulsion under different friction conditions were studied. The lubricating mechanism was revealed and the biological activities were evaluated. Results showed that the prepared Pickering emulsion displayed superior lubrication property at the Ti6Al4V biological material interface. The maximum friction reduction and anti-wear abilities of the Pickering emulsion were improved by 36% and 50% compared to water, respectively. This was primarily due to the action of the double-layer lubrication films composed of the graphene oxide and angelica essential oil molecules. It was worth noting that the friction reduction effect of the Pickering emulsion at the natural cartilage interface was higher about 19% than that of HA used in clinic for OA commonly. In addition, the Pickering emulsion also displayed antioxidant activity and cell biocompatibility, showing a good clinical application prospect in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microbially mediated Fe(II) oxidation has a great potential for attenuating arsenic (As) mobility in an anoxic groundwaters. Green rust (GR), a common Fe(II)-bearing phase in such environments, could be easily oxidized into Fe (oxyhydr)oxides through microbial activity. This study focused on Acidovorax sp. strain BoFeN1, an anaerobic nitrate-reducing Fe(II)-oxidizing (NRFO) bacterium, to promote the transformation of GR. In biotic GR transformation experiments, magnetite formation occurred at [As] ini  = 5 mg/L while lepidocrocite and goethite were formed at [As] ini  = 10 mg/L. In the absence of bacterium, the GR persisted throughout the 120-h experiment. Meanwhile, with the addition of strain BoFeN1, the final aqueous As concentration significantly decreased from 0.237 to 0.004 mg/L (C 0  = 5 mg/L) and from 1.457 to 0.096 mg/L (C 0  = 10 mg/L) at 120 h. It was indicated that strain BoFeN1 played a crucial role in promoting the GR transformation and enhancing As immobilization. Further investigations revealed that the role of strain BoFeN1 extended beyond Fe-oxidation. With nitrite (the intermediate of nitrate bioreduction) as oxidizer, lepidocrocite/goethite were formed in the chemical-oxidation system, excluding magnetite. In the Bio - [As] ini  = 5 mg/L, the occurrence of lepidocrocite via the bio-oxidation of Fe(II) in GR at 24 h, along with the metabolism of strain BoFeN1 reducing nitrate accompanied with H + consumption, it should be reasonably deduced that the alkaline micro-environment of periplasm induced by strain BoFeN1 were vital for the transformation of lepidocrocite to magnetite triggered by trace Fe(II). However, in the Bio - [As] ini  = 10 mg/L, more As adsorbed on GR inhibiting the adsorption of bacterium, so the alkaline micro-environment had no obvious effect on such transformation. This study helps to understand the interdependence between GR and anaerobic NRFO bacterium, and provides a new perspective for more effective As remediation strategies in anoxic groundwaters., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Reduced-toxicity conditioning (RIC) regimens are used for allogeneic hematopoietic stem cell transplantation in older patients. However, successful outcomes are hindered by graft-versus-host disease (GVHD), treatment-related mortality, and relapse, particularly after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT). The aim of this study was to evaluate the effectiveness of an RIC conditioning regimen that included a combination of cyclosporin A, methotrexate (on day + 1), mycophenolate, lower doses of post-transplantation PTCy (40 mg/kg on day + 3), and ATG (7.5 mg/kg) as GVHD prophylaxis prior to haplo-stem cell transplantation (haplo-SCT) in older patients., Methods: We retrospectively analyzed outcomes in 55 patients ≥ 55 years of age with hematologic malignancies treated with fludarabine, cytarabine, busulfan, and low-dose cyclophosphamide as the conditioning regimen between January 1, 2019, and November 30, 2023., Results: Neutrophil engraftment was successful in all patients within 28 days, with 54 patients (98.2%) achieving complete donor chimerism. The cumulative incidence of non-relapse mortality was 0% at 30 days, 7.5% at 100 days, and 19% at 1 year. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 25% (95%CI, 15-38%), whereas that of grade III-IV aGVHD was 9.1% (95% CI, 3.3-19%). The cumulative incidence of extensive chronic graft-versus-host disease at 1 year was 3.6% (95%CI, 0.66-11%). The cumulative incidences of relapse, overall survival, and GVHD-free/relapse-free survival at 1 year were 9.0%, 71.6%, and 67.1%, respectively., Conclusions: An RIC conditioning regimen, including a combination of lower PTCy/ATG as GVHD prophylaxis, followed by haplo-SCT, might be a promising option for appropriately selected older patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance., Methods: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo., Results: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo., Conclusion: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers., (© 2024. The Author(s).)

The rise of large-scale Transformers has led to challenges regarding computational costs and energy consumption. In this context, spiking neural networks (SNNs) offer potential solutions due to their energy efficiency and processing speed. However, the inaccuracy of surrogate gradients and feature space quantization pose challenges for directly training deep SNN Transformers. To tackle these challenges, we propose a method (called LDD) to align ANN and SNN features across different abstraction levels in a Transformer network. LDD incorporates structured feature knowledge from ANNs to guide SNN training, ensuring the preservation of crucial information and addressing inaccuracies in surrogate gradients through designing layer-wise distillation losses. The proposed approach outperforms existing methods on the CIFAR10 (96.1%), CIFAR100 (82.3%), and ImageNet (80.9%) datasets, and enables training of the deepest SNN Transformer network using ImageNet.